Adaptive randomization of veliparib-carboplatin treatment in breast cancer

the I-SPY 2 Investigators

Research output: Contribution to journalArticle

191 Citations (Scopus)

Abstract

BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib- carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Original languageEnglish (US)
Pages (from-to)23-34
Number of pages12
JournalNew England Journal of Medicine
Volume375
Issue number1
DOIs
StatePublished - Jul 7 2016

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Carboplatin
Random Allocation
Breast Neoplasms
Biomarkers
Triple Negative Breast Neoplasms
Therapeutics
Neoplasms
Drug Therapy
Genetic Heterogeneity
veliparib
Tumor Burden
Magnetic Resonance Imaging
Hormones
Delivery of Health Care
Control Groups
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Adaptive randomization of veliparib-carboplatin treatment in breast cancer. / the I-SPY 2 Investigators.

In: New England Journal of Medicine, Vol. 375, No. 1, 07.07.2016, p. 23-34.

Research output: Contribution to journalArticle

the I-SPY 2 Investigators. / Adaptive randomization of veliparib-carboplatin treatment in breast cancer. In: New England Journal of Medicine. 2016 ; Vol. 375, No. 1. pp. 23-34.
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abstract = "BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88{\%} predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51{\%} (95{\%} Bayesian probability interval [PI], 36 to 66{\%}) in the veliparib-carboplatin group versus 26{\%} (95{\%} PI, 9 to 43{\%}) in the control group. The toxicity of veliparib- carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).",
author = "{the I-SPY 2 Investigators} and Rugo, {Hope S.} and Olopade, {Olufunmilayo I.} and Angela DeMichele and Christina Yau and {Van't Veer}, {Laura J.} and Buxton, {Meredith B.} and Michael Hogarth and Hylton, {Nola M.} and Melissa Paoloni and Jane Perlmutter and Symmans, {W. Fraser} and Douglas Yee and Chien, {A. Jo} and Wallace, {Anne M.} and Kaplan, {Henry G.} and Boughey, {Judy C.} and Haddad, {Tufia C.} and Albain, {Kathy S.} and Liu, {Minetta C.} and Claudine Isaacs and Khan, {Qamar J.} and Lang, {Julie E.} and Viscusi, {Rebecca K.} and Lajos Pusztai and Moulder, {Stacy L.} and Chui, {Stephen (Steve)} and Kathleen Kemmer and Elias, {Anthony D.} and Edmiston, {Kirsten K.} and Euhus, {David M.} and Haley, {Barbara B.} and Rita Nanda and Northfelt, {Donald W.} and Debasish Tripathy and Wood, {William C.} and Cheryl Ewing and Richard Schwab and Julia Lyandres and Davis, {Sarah E.} and Hirst, {Gillian L.} and Ashish Sanil and Berry, {Donald A.} and Esserman, {Laura J.}",
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T1 - Adaptive randomization of veliparib-carboplatin treatment in breast cancer

AU - the I-SPY 2 Investigators

AU - Rugo, Hope S.

AU - Olopade, Olufunmilayo I.

AU - DeMichele, Angela

AU - Yau, Christina

AU - Van't Veer, Laura J.

AU - Buxton, Meredith B.

AU - Hogarth, Michael

AU - Hylton, Nola M.

AU - Paoloni, Melissa

AU - Perlmutter, Jane

AU - Symmans, W. Fraser

AU - Yee, Douglas

AU - Chien, A. Jo

AU - Wallace, Anne M.

AU - Kaplan, Henry G.

AU - Boughey, Judy C.

AU - Haddad, Tufia C.

AU - Albain, Kathy S.

AU - Liu, Minetta C.

AU - Isaacs, Claudine

AU - Khan, Qamar J.

AU - Lang, Julie E.

AU - Viscusi, Rebecca K.

AU - Pusztai, Lajos

AU - Moulder, Stacy L.

AU - Chui, Stephen (Steve)

AU - Kemmer, Kathleen

AU - Elias, Anthony D.

AU - Edmiston, Kirsten K.

AU - Euhus, David M.

AU - Haley, Barbara B.

AU - Nanda, Rita

AU - Northfelt, Donald W.

AU - Tripathy, Debasish

AU - Wood, William C.

AU - Ewing, Cheryl

AU - Schwab, Richard

AU - Lyandres, Julia

AU - Davis, Sarah E.

AU - Hirst, Gillian L.

AU - Sanil, Ashish

AU - Berry, Donald A.

AU - Esserman, Laura J.

PY - 2016/7/7

Y1 - 2016/7/7

N2 - BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib- carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

AB - BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib- carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

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